Endothelin is a 21-amino acid peptide produced by endothelial cells. The peptide is secreted not only by endothelial cells but also by tracheal epithelial cells or from kidney cells. Endothelin (ET-1) has a potent vasoconstrictor effect. The vasoconstricting effect is caused by the binding of endothelin to its receptor on the vascular smooth muscle cells..sup.1, 2, 3
Endothelin-1 (ET-1) is one of three recently identified potent vasoconstricting peptides which also includes endothelin-2 (ET-2) and endothelin-3 (ET-3) which differ from ET-1 by two and six amine acids, respectively..sup.4
Increased levels of endothelin are found in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease or atherosclerosis or in the washing fluids of the respiratory tract of patients with asthma as compared to normal levels..sup.5, 6, 7, 8
An experimental model of a cerebral vasespasm and a second model of acute renal failure have led to the conclusion that endothelin is one of the mediators causing cerebral vasespasms following a subarachnoid hemorrhage, and renal failure..sup.9, 10
Endothelin was also found to control the release of many physiological substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A2,.sup.14, prostacyclin, norepinephrine, angiotensin II and substance P..sup.11, 12, 13, 14, 15, 16 Further, endothelin causes contraction of the smooth muscle of gastrointestinal tract and the uterine smooth muscle..sup.17, 18, 19 Endothelin has also been shown to promote the growth of rat vascular smooth muscle cells which would suggest a possible relevance to arterial hypertrophy..sup.20
Endothelin receptors are present in high concentration not only in the peripheral tissues but also in the central nervous system, and cerebral administration of endothelin has been shown to induce behavioral changes in animals, suggesting endothelin plays an important role for controlling neural functions..sup.21
Endotoxin has been shown to promote the release of endothelin. This finding has suggested that endothelin is one important mediator for endotoxin-induced diseases..sup.22, 23
A study has shown that when cyclosporin added to a renal cell culture increased endothelin secretion is observed..sup.24 Another study has shown that when cyclosporin was admininstered to rats, a decrease in the glomerular filtration rate and an increase in the blood pressure were observed, in association with a remarkable increase in the circulating endothelin level. This cyclosporin-induced renal failure can be suppressed by the administration of endothelin antibody..sup.25 These studies suggest that endothelin is significantly involved in the pathogenesis of cyclosporin-induced diseases.
A recent study in patients with congestive heart failure demonstrated a good correlation between the elevated levels of endothelin in the plasma and the severity of the disease..sup.26
Substances which specifically inhibit the binding of endothelin to its receptor are believed to antagonize the above mentioned physiological activities of endothelin and thereby would be expected to be a useful method of treatment for a person in need of such treatment. The present invention discloses potent non-peptidic endothelin antagonists.
Endothelin is an endogenous substance which directly or indirectly (through the controlled release of various other endogenous substances) induces sustained contraction of vascular or non-vascular smooth muscles and its excess production or excess secretion is believed to be one of the pathogeneses for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, acute renal failure, myocardial infarction, angina pectoris, arteriosclerosis, cerebral vasospasm and cerebral infarction.
The novel compound of the present invention is useful as a non-peptidic endothelin antagonist, which have not been disclosed in any issued patents or any known patent applications. Fujisawa in European Patent Application EP 457,195, Banyu in EP 436, 189 and 460,679, and Takeda in Patent Cooperation Treaty International Publication No. WO 91/13089 have applications disclosing linear and cyclic peptidic compounds as endothelin antagonists. Fujisawa has also disclosed anthraquinone derivatives produced by a fermentation process using Streptomyces sp. No. 89009 in EP 405,421.
A Roussel-Uclaf European Patent Application (EP 498,723) disclosed a series of substituted (1,4-quinolinoxy)methylbiphenylcarboxylic acids as both endothelin antagonists and angiotensin H antagonists. A patent from Roche (EP 510,526) has also appeared claiming endothelin antagonists properties of a series of N-(4-pyrimidinyl)benzenesulfonamides.